CN109912625A - A kind of process reducing cefotaxime impurity H - Google Patents
A kind of process reducing cefotaxime impurity H Download PDFInfo
- Publication number
- CN109912625A CN109912625A CN201910160018.0A CN201910160018A CN109912625A CN 109912625 A CN109912625 A CN 109912625A CN 201910160018 A CN201910160018 A CN 201910160018A CN 109912625 A CN109912625 A CN 109912625A
- Authority
- CN
- China
- Prior art keywords
- cefotaxime
- tert
- butyl ester
- preparation
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The present invention provides a kind of processes for reducing cefotaxime impurity H, it is characterized by: with one or more of methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile, 2- methyltetrahydrofuran for main solvent, use the mixed solvent of the tert-butyl alcohol or the tert-butyl alcohol and methanol for cosolvent, under alkaline condition, 7-APCA and his pyridine activity ester condensation reaction is set to generate the cefotaxime tert-butyl ester, after water process, solvent crystallization obtains the cefotaxime tert-butyl ester.For its impurity cefotaxime methyl esters (H) of the product of this method acquisition less than 0.1%, unknown impuritie can be controlled in 0.05% or less.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular, to a kind of preparation method of antibacterials cefotaxime.
Background technique
Cefotaxime chemical name is (6R, 7R) -7- [[(2Z) -2- (2- amino -1,3- thiazole -4- base) -2- (1- hydroxyl
Base-2- methyl-1-oxopropan-2- base) oxygen imido acetyl] amino]-8- oxo-3- (pyridine-1--1- ylmethyl)-5-
Thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid.For third generation injection cephalosporin antibiotic product.
According to the structural analysis of the cefotaxime methyl esters (H) of EP pharmacopeia storage, in the preparation process of cefotaxime most
It is possible that generating the impurity is to have micro be somebody's turn to do in synthesis cefotaxime tert-butyl ester process procedure or cefotaxime active ester raw material
Impurity.It is confirmed by research papers, no matter in his pyridine activity Lipase absobed or will in his pyridine tert-butyl ester synthesis process
Control the use of solvent methanol.The structure of cefotaxime impurity H is (6R, 7R) -7- [[(2- amino -1,3,4- thiophene
Azoles-4- base)-2- (alkane-2- base in 2-methyl-1 of 1- methoxyl group-oxo) oxygen imido acetyl] amino]-8- oxygen
Generation -3- (pyridine -1--1- base-methyl) -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2-
Formic acid;The impurity is by zebrafish embryo toxicity test, and discovery teratogenesis is 25 times of cefotaxime, lethal effect is cephalo
8 times of his pyridine.So cefotaxime impurity H should give strict control.
Domestic synthesis cefotaxime is mainly 7-amino-cephalosporanic acid and silylating reagent in methylene chloride solvent at present
Reflux first carries out the protection of aminocarboxylic base, then forms iodo object with Iodotrimethylsilane and synthesizes again with pyridine in 7-APCA tri-
Mesosome.7-APCA is condensed into his the pyridine tert-butyl ester under his pyridine active ester alkaline condition in the organic solvents such as methylene chloride/methanol,
His the pyridine tert-butyl ester is acidified in formic acid/hydrochloric acid mixed solution forms his thiamine hydrochloride, he uses thiamine hydrochloride in appropriate water for injection
Then diluted alkaline tune PH dissolution is acidified crystallization and obtains target product cefotaxime.
The above process, generate cefotaxime methyl esters (H) process be exactly in the synthesis of his pyridine tert-butyl ester solvent methanol make
Ester exchange reaction occurs with the tert-butyl and methanol that cause in seven side chains to generate.Seven sides of US005831085A patent report
Chain does not have to his pyridine activity ester condensation, is condensed using acyl chlorides reagent.I.e. his pyridine side-chain acid synthesizes acyl chlorides preparation with DFCCS, then exists
His the pyridine tert-butyl ester is synthesized under cryogenic conditions with 7-APCA, entire technical process requires ultralow temperature reaction, and control of industrialization difficulty is big
It is at high cost, and acyl chlorides preparation is unstable.
Summary of the invention
Present invention aims to overcome that shortcoming present in above-mentioned technology, 7-APCA still uses domestic at present general
Stable industrialization process, 7-APCA is in methylene chloride, chloroform, tetrahydrofuran, acetonitrile, carbon tetrachloride, 2- methyl tetrahydro
Furans etc. is condensed into his the pyridine tert-butyl ester with the in the mixed solvent of the tert-butyl alcohol or methanol and his pyridine active ester, and Pure water preparation is then added
Afterwards, solvent crystallization.At salt in the mixed liquor of formic acid and hydrochloric acid, acetone crystallization obtains the cefotaxime tert-butyl ester synthesized with the technique
To his thiamine hydrochloride of cephalo, through liquid phase analysis cefotaxime methyl esters (H) less than 0.1%.Continue to synthesize ceftazidime pentahydrate,
Through the liquid phase analysis impurity still less than 0.1%.And the product of the domestic cefotaxime manufacturer impurity is generally greater than 0.2%,
So controlling the critical process link of impurity generation with this patent process, hence it is evident that improve the quality of cefotaxime, drop
The low adverse reaction and toxic side effect of drug.
In order to achieve the above object, the present invention provides a kind of preparation methods of cefotaxime tert-butyl ester, it is characterised in that:
It is molten based on one or more of methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, acetonitrile, 2- methyltetrahydrofuran
Agent uses the mixed solvent of the tert-butyl alcohol or the tert-butyl alcohol and methanol for cosolvent, under alkaline condition, keeps 7-APCA and his pyridine active
Ester condensation reaction generates the cefotaxime tert-butyl ester, and after water process, solvent crystallization obtains the cefotaxime tert-butyl ester.
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., the molar ratio of above-mentioned 7-APCA and his pyridine active ester is 1:1.05-1.25;Preferably 1:1.15-1.20;Weight ratio is
1.4-1.5。
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., above-mentioned cosolvent dosage is the 10%-20% of 7-APCA and his pyridine active ester total weight.
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., the volume ratio of above-mentioned main solvent and cosolvent is 10-25:1.
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., when cosolvent is the mixed solvent of the tert-butyl alcohol and methanol,
The volume ratio of the above-mentioned tert-butyl alcohol and methanol is 5-10:1.
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., specific process step is as follows:
S1. it in main solvent, after cosolvent is added, is cooled at a temperature of 0-10 DEG C, addition 7-APCA and his pyridine are active
After ester, adjusting pH is 7-9, and temperature control reacts 20-24 hours;
S2. after Pure water preparation reaction solution 1-2 hours, the cefotaxime tert-butyl ester is obtained after solvent crystallization, washing procedure.
The reaction equation of above-mentioned reaction process is as follows:
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., the reagent for adjusting pH is alkaline agent, selects polyamine, such as: one of triethylamine, diethylamine, ethylenediamine, DMF or several
Kind.
Further, the preparation method of a kind of cefotaxime tert-butyl ester provided by the invention, also has a characteristic that
I.e., the solvent of above-mentioned crystallization and the reagent of washing are in the alcohols of pure water, carbon atom number greater than 2, ketone, ether solvent
One or more.
In addition, the present invention also provides a kind of preparation methods of cefotaxime hydrochloride, it is characterised in that: in formic acid and salt
In the mixed solution of acid, the cefotaxime tert-butyl ester such as the preparation of claim 1-8 either method is added, in 15-20 DEG C of reaction
At a temperature of react 2-5 hours after, select organic reagent crystallization obtain cefotaxime hydrochloride;
Wherein, the volume ratio of above-mentioned formic acid and hydrochloric acid is 1:0.5-1;
The amount ratio of the mixed solution of above-mentioned formic acid and hydrochloric acid and the cefotaxime tert-butyl ester are as follows: every milliliter of formic acid and hydrochloric acid
Mixed solution adds 0.6-1.5 grams of the cefotaxime tert-butyl ester;
Above-mentioned organic reagent is selected from alcohols (propyl alcohol, butanol, isopropanol etc.) of the carbon atom number greater than 2, ketone (acetone
Deng), one or more of ether solvent (ether, second diether, tetrahydrofuran, dioxane etc.).
The reaction equation of above-mentioned reaction process is as follows:
In addition, the present invention also provides a kind of preparation methods of ceftazidime pentahydrate, it is characterised in that:
S1. after mixing in water and organic solvent, the cefotaxime hydrochloride as prepared by claim 9 is added;
S2. adjusting pH is that 6.0-6.5 makes its dissolved clarification;
S3. it adds bleaching agent bleaching 5-15 minutes;
S4. it is complete to crystallization that phosphoric acid is added dropwise, obtains ceftazidime pentahydrate.
The reaction equation of above-mentioned reaction is as follows:
The function and effect of the present invention:
Cefotaxime content using the method for the present invention production is high, and color grade is good, it is known that impurity cefotaxime methyl esters (H) is small
In 0.1%, unknown impuritie can be controlled in 0.05% or less;In the method for the invention, subtract when synthesizing the cefotaxime tert-butyl ester
Few methanol or the use for replacing methanol, are reduced or avoided the generation of cefotaxime methyl esters.Reaction terminates, then through washing at purification
Reason, solvent crystallization, centrifugation Shi Zaiyong solvent wash material, obtain cefotaxime tert-butyl ester product.Cefotaxime salt is synthesized with the product
Hydrochlorate and his pyridine pentahydrate, are substantially reduced through analysing impurity cefotaxime methyl esters (H).Technical process reaction condition is mildly easy
Control, be suitble to industrialized production, hence it is evident that improve product quality, improve product competitiveness in the market, to drug safety have into
One step guarantee.
Detailed description of the invention
Fig. 1, embodiment 1-2 map;
Fig. 2, embodiment 1-3 map;
Fig. 3, embodiment 2-2 map;
Fig. 4, embodiment 2-3 map;
Fig. 5, embodiment 3-2 map;
Fig. 6, embodiment 3-3 map.
Specific embodiment
Embodiment 1-1,
Chloroform 520ml is added in four mouthfuls of reaction flasks of clean dried, tert-butyl alcohol 30ml is added, is cooled to 0-5 DEG C.
7-APCA 70g is added, he is pyridine active ester 105g, and triethylamine is added dropwise in control temperature, adjusts PH to 7.0-9.0.0-10 DEG C of temperature control anti-
It answers 20-24 hours.Reaction is finished, and pure water 150ml is added, and is stirred 1-2 hours, is separated chloroform.Isopropanol analysis is instilled in medical fluid
The cefotaxime tert-butyl ester out, 0-10 DEG C stirring growing the grain 2 hours.It filters, is washed with isopropanol, the cefotaxime tert-butyl ester is obtained after drying
Dry product.
Weight yield: 145%, purity 98.9%,
Embodiment 1-2,
Formic acid 54ml is added in four mouthfuls of reaction flasks of clean dried, concentrated hydrochloric acid 36ml is stirred.Cefotaxime is added
Tert-butyl ester 60g, 15-20 DEG C is reacted 3 hours, and room temperature is added dropwise acetone to his thiamine hydrochloride and is precipitated completely.0-10 DEG C growing the grain 2 hours.
It filters, with acetone washing, cefotaxime hydrochloric acid dried salted products is obtained after drying.
Weight yield: 88%, purity 99.3%, H:0.07%.
Embodiment 1-3,
Water for injection 20ml is added in four mouthfuls of reaction flasks of clean dried, acetone 30ml is stirred.Be added cephalo he
4N NaOH is added dropwise in thiamine hydrochloride 50g, and PH to 6.0-6.5 is adjusted to make its dissolved clarification.Active carbon 1g is added after dissolved clarification, decolourizes 10 minutes.
Filtering, filtrate added drop-wise 4M H3PO4, until crystal is precipitated completely.0-10 DEG C stirring growing the grain 1 hour.It filters, with acetone washing, drying
Ceftazidime pentahydrate dry product is obtained afterwards.
Weight yield: 80%, purity 99.6%, H:0.06%.
Embodiment 2-1,
Methylene chloride 300ml is added in four mouthfuls of reaction flasks of clean dried, tert-butyl alcohol 13ml is added, is cooled to 0-5 DEG C.
7-APCA 35g is added, he is pyridine active ester 50g, and triethylamine is added dropwise in control temperature, adjusts PH to 7.0-9.0.0-10 DEG C of temperature control reaction
20-24 hours.Reaction is finished, and pure water 50ml is added, and is stirred 1-2 hours, is separated methylene chloride.Acetone is instilled in medical fluid, and cephalo is precipitated
His pyridine tert-butyl ester, 0-10 DEG C stirring growing the grain 2 hours.It filters, with acetone washing, cefotaxime tert-butyl ester dry product is obtained after drying.
Weight yield: 148%, purity 98.8%,
Embodiment 2-2,
Formic acid 54ml is added in four mouthfuls of reaction flasks of clean dried, concentrated hydrochloric acid 36ml is stirred.Cefotaxime is added
Tert-butyl ester 60g, 15-20 DEG C is reacted 3 hours, and room temperature is added dropwise acetone to his thiamine hydrochloride and is precipitated completely.0-10 DEG C growing the grain 2 hours.
It filters, with acetone washing, cefotaxime hydrochloric acid dried salted products is obtained after drying.
Weight yield: 89%, purity 99.2%, H:0.02%.
Embodiment 2-3,
Water for injection 20ml is added in four mouthfuls of reaction flasks of clean dried, acetone 30ml is stirred.Be added cephalo he
4N NaOH is added dropwise in thiamine hydrochloride 50g, and PH to 6.0-6.5 is adjusted to make its dissolved clarification.Active carbon 1g is added after dissolved clarification, decolourizes 10 minutes.
Filtering, filtrate added drop-wise 4M H3PO4, until crystal is precipitated completely.0-10 DEG C stirring growing the grain 1 hour.It filters, with acetone washing, drying
Ceftazidime pentahydrate dry product is obtained afterwards.
Weight yield: 83%, purity 99.5%, H:0.08%.
Embodiment 3-1,
2- methyltetrahydrofuran 500ml is added in four mouthfuls of reaction flasks of clean dried, tert-butyl alcohol 20ml/ methanol is added
10ml is cooled to 0-5 DEG C.7-APCA 70g is added, he is pyridine active ester 105g, and DMF is added dropwise in control temperature, adjusts PH to 7.0-
9.0.Reaction 20-24 hours of 0-10 DEG C of temperature control.Reaction is finished, and pure water 200ml is added, and is stirred 1-2 hours, is separated 2- methyl tetrahydro furan
It mutters.In medical fluid instill isopropanol be precipitated the cefotaxime tert-butyl ester, 0-10 DEG C stirring growing the grain 2 hours.It filters, is washed with isopropanol,
Cefotaxime tert-butyl ester dry product is obtained after drying.
Weight yield: 143%, purity 98.6%,
Embodiment 3-2,
Formic acid 54ml is added in four mouthfuls of reaction flasks of clean dried, concentrated hydrochloric acid 36ml is stirred.Cefotaxime is added
Tert-butyl ester 60g, 15-20 DEG C is reacted 3 hours, and room temperature is added dropwise acetone to his thiamine hydrochloride and is precipitated completely.0-10 DEG C growing the grain 2 hours.
It filters, with acetone washing, cefotaxime hydrochloric acid dried salted products is obtained after drying.
Weight yield: 90%, purity 99.4%, H:0.02%.
Embodiment 3-3,
Water for injection 20ml is added in four mouthfuls of reaction flasks of clean dried, acetone 30ml is stirred.Be added cephalo he
4N NaOH is added dropwise in thiamine hydrochloride 50g, and PH to 6.0-6.5 is adjusted to make its dissolved clarification.Active carbon 1g is added after dissolved clarification, decolourizes 10 minutes.
Filtering, filtrate added drop-wise 4M H3PO4, until crystal is precipitated completely.0-10 DEG C stirring growing the grain 1 hour.It filters, with acetone washing, drying
Ceftazidime pentahydrate dry product is obtained afterwards.
Weight yield: 81%, purity 99.8%, H:0.02%.
Claims (10)
1. a kind of preparation method of the cefotaxime tert-butyl ester, it is characterised in that: with methylene chloride, chloroform, carbon tetrachloride, four
One or more of hydrogen furans, acetonitrile, 2- methyltetrahydrofuran are main solvent, using the mixed of the tert-butyl alcohol or the tert-butyl alcohol and methanol
Bonding solvent is cosolvent, under alkaline condition, 7-APCA and his pyridine activity ester condensation reaction is made to generate the cefotaxime tert-butyl ester, warp
After water process, solvent crystallization obtains the cefotaxime tert-butyl ester.
2. a kind of preparation method of the cefotaxime tert-butyl ester as described in claim 1, it is characterised in that: the 7-APCA and he
The molar ratio of pyridine active ester is 1:1.05-1.25;Preferably 1:1.15-1.20;Weight ratio is 1.4-1.5.
3. a kind of preparation method of the cefotaxime tert-butyl ester as described in claim 1, it is characterised in that: the cosolvent dosage
For the 10%-20% of 7-APCA and his pyridine active ester total weight.
4. a kind of preparation method of the cefotaxime tert-butyl ester as described in claim 1, it is characterised in that:
The volume ratio of the main solvent and cosolvent is 10-25:1.
5. a kind of preparation method of the cefotaxime tert-butyl ester as described in claim 1, it is characterised in that:
When cosolvent is the mixed solvent of the tert-butyl alcohol and methanol,
The volume ratio of the tert-butyl alcohol and methanol is 5-10:1.
6. a kind of preparation method of the cefotaxime tert-butyl ester as described in claim 1, which is characterized in that specific process step is such as
Shown in lower:
S1. it in main solvent, after cosolvent is added, is cooled at a temperature of 0-10 DEG C, after adding 7-APCA and his pyridine active ester,
Adjusting pH is 7-9, and temperature control reacts 20-24 hours;
S2. after Pure water preparation reaction solution 1-2 hours, the cefotaxime tert-butyl ester is obtained after solvent crystallization, washing procedure.
7. a kind of preparation method of the cefotaxime tert-butyl ester as claimed in claim 6, it is characterised in that: the reagent for adjusting pH is
One or more of triethylamine, diethylamine, ethylenediamine, DMF.
8. a kind of preparation method of the cefotaxime tert-butyl ester as claimed in claim 6, it is characterised in that: the solvent of the crystallization
And the reagent of washing is selected from one or more of the alcohols of pure water, carbon atom number greater than 2, ketone, ether solvent.
9. a kind of preparation method of cefotaxime hydrochloride, it is characterised in that:
In the mixed solution of formic acid and hydrochloric acid, the cefotaxime tert-butyl ester such as the preparation of claim 1-8 either method is added, in
After reacting 2-5 hours under 15-20 DEG C of reaction temperature, organic reagent crystallization is selected to obtain cefotaxime hydrochloride;
Wherein, the volume ratio of the formic acid and hydrochloric acid is 1:0.5-1;
The amount ratio of the mixed solution of the formic acid and hydrochloric acid and the cefotaxime tert-butyl ester are as follows: the mixing of every milliliter of formic acid and hydrochloric acid
Solution adds 0.6-1.5 grams of the cefotaxime tert-butyl ester;
The organic reagent is selected from one or more of alcohols of the carbon atom number greater than 2, ketone, ether solvent.
10. a kind of preparation method of ceftazidime pentahydrate, it is characterised in that:
S1. after mixing in water and organic solvent, the cefotaxime hydrochloride as prepared by claim 9 is added;
S2. adjusting pH is that 6.0-6.5 makes its dissolved clarification;
S3. it adds bleaching agent bleaching 5-15 minutes;
S4. it is complete to crystallization that phosphoric acid is added dropwise, obtains ceftazidime pentahydrate.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910160018.0A CN109912625B (en) | 2019-03-04 | 2019-03-04 | Process method for reducing ceftazidime impurity H |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910160018.0A CN109912625B (en) | 2019-03-04 | 2019-03-04 | Process method for reducing ceftazidime impurity H |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109912625A true CN109912625A (en) | 2019-06-21 |
CN109912625B CN109912625B (en) | 2021-01-12 |
Family
ID=66963041
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910160018.0A Active CN109912625B (en) | 2019-03-04 | 2019-03-04 | Process method for reducing ceftazidime impurity H |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109912625B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113583023A (en) * | 2021-06-24 | 2021-11-02 | 山东睿智医药科技有限公司 | Process method for preventing ceftazidime tert-butyl ester from generating ceftazidime H impurities |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102286003A (en) * | 2011-08-05 | 2011-12-21 | 哈药集团制药总厂 | Synthesis method of ceftazidime |
CN102391289A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
CN103030651A (en) * | 2012-12-25 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
CN106336418A (en) * | 2016-08-19 | 2017-01-18 | 上海上药新亚药业有限公司 | Solid phase synthesis method of ceftazidime hydrochloride |
-
2019
- 2019-03-04 CN CN201910160018.0A patent/CN109912625B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102286003A (en) * | 2011-08-05 | 2011-12-21 | 哈药集团制药总厂 | Synthesis method of ceftazidime |
CN102391289A (en) * | 2011-12-03 | 2012-03-28 | 齐鲁安替制药有限公司 | Synthetic methods of ceftazidime intermediate and ceftazidime |
CN103030651A (en) * | 2012-12-25 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing ceftazidime hydrochloride |
CN106336418A (en) * | 2016-08-19 | 2017-01-18 | 上海上药新亚药业有限公司 | Solid phase synthesis method of ceftazidime hydrochloride |
Non-Patent Citations (1)
Title |
---|
厉昆,等: "头孢他啶侧链活性酯中一个未知杂质的合成和确认", 《精细化工中间体》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113583023A (en) * | 2021-06-24 | 2021-11-02 | 山东睿智医药科技有限公司 | Process method for preventing ceftazidime tert-butyl ester from generating ceftazidime H impurities |
Also Published As
Publication number | Publication date |
---|---|
CN109912625B (en) | 2021-01-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101007812B (en) | Antibacterial drugs cefoxitin preparation process | |
CN111170855B (en) | Compound and method for synthesizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid by using same | |
CN101613361B (en) | Method for preparing cefoxitin sodium | |
CN107501265B (en) | A kind of 7- oxo-diazabicylo [3,2,1] octane derivatives compound and its preparation method and application | |
KR20080064990A (en) | Process for the preparation of cefdinir | |
CN108947881B (en) | Method for preparing optically pure L-type selenium-methyl selenocysteine | |
CN109912625A (en) | A kind of process reducing cefotaxime impurity H | |
US5831086A (en) | Production of cefotaxime and new sodium salts | |
CN101337970B (en) | Method for synthesizing antibiotic cefpirome sulfate | |
CN114409677B (en) | Preparation method of high-purity cefotaxime acid | |
CN105440054B (en) | A kind of technique preparing cefathiamidine | |
CN107266473A (en) | A kind of synthetic method of cefotaxime | |
CN108084213B (en) | Preparation method of cefazedone sodium compound | |
CN113025679B (en) | Enzymatic preparation process of cefcapene precursor acid of t-butyloxycarbonyl | |
CN111533710B (en) | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method | |
CN110128412B (en) | Preparation method of dextro-ilaprazole potassium salt mother liquor, dextro-ilaprazole and preparation method thereof | |
CN110241167B (en) | Method for preparing cefamandole nafate derivative by enzyme method | |
CN111187255B (en) | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole | |
CN111925298B (en) | 4-CNAB and preparation method thereof | |
CN112480026B (en) | Method for producing AE-active esters | |
CN112300198B (en) | Synthesis method of cefixime and cefixime ester | |
CN109776448B (en) | Preparation method of febuxostat crystal form A | |
CN107955021A (en) | A kind of production method of the Ceftriaxone Sodium of low impurity | |
CN106432182B (en) | Specially the synthetic method of azoles amine intermediate | |
CN108084064B (en) | Novel preparation method of D- (-) -tartaric acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |